(1) Field of the Invention
The present invention relates to a process for the preparation of R.alpha.-cyclopentenones and thereafter R.alpha., R.omega.-cyclopentanoids, particularly prostaglandins (PGs). The process involves the reaction of a protected 4-hydroxy .alpha.-iodo or .alpha.-bromoenone with an alkylborane to produce the R.alpha.-cyclopentenone. The R.alpha.-cyclopentenone is reacted with a cuprate or other R.alpha.-organometallics to provide a cyclopentanoid of the formula: ##STR2## P is a protecting group which is removed by conventional methods to provide the 4-hydroxy group.
(2) Background of the Invention
General and efficient syntheses of prostaglandins (PGs) have been the subject of much effort over the past three decades (Collins, P. W., et al., Chem. Rev. 93, 1533 (1993)). Aside from the widely applied, but lengthy, Corey synthesis (Corey, E. J., et al., J. Am. Chem. Soc., 91, 5675 (1969)), two other popular approaches have emerged from these efforts: the three-component coupling process (Noyori, R., et al. Angew. Chem., Int. Ed. Engl., 23, 847 (1984); and Noyori, R., et al., J. Am. Chem. Soc. 110, 4718 (1988); Noyori, R., et al, Chemtracts: Org. Chem., 173 (1990); and Johnson, C. R., et al., J. Am. Chem. Soc. 110, 4726 (1988)) and the two-component (conjugate addition) process (Sih, C. J., et al., J. Am. Chem. Soc. 94, 3643 (1972); and Sato, F., et al., Tetrahedron Lett., 31, 4481 (1990)). ##STR3## The one-pot three-component coupling synthesis Equation (1) is one of the most direct means of assembling PGs. The use of (R)-4-(tert-butyldimethylsiloxy)-2-cyclopentenone (compound 1a) as an enantiopure component in this process is a particular advantage due to its ease of preparation (Noyori, R., et al., J. Am. Chem. Soc., 110, 4718 (1988)). Despite the attractiveness of this approach and the improvements which have been made upon it, (Gooding, O. W., et al., J. Org. Chem. 58, 3681 (1993); and Morita, Y., et al., J. Org. Chem., 54, 1785 (1989)), several limitations still exist. Most important are the problems of enolate equilibrium and .beta.-alkoxide elimination associated with alkylation of the intermediate enolate, problems which are especially evident when trapping with unactivated electrophiles such as a halide corresponding to the .alpha.-chain of PGE.sub.1. As a result, the two component synthesis (conjugate addition of R.omega. to a 4(R)-alkoxy-2-alkyl-2-cyclopentenone, Equation 2 has remained a highly studied and valuable route to PGs. The limiting factor of this approach has been the availability of the enantiopure .alpha.alkylcyclopentenones (compound 2) (Babiak, K. A., et al., J. Org. Chem. 55, 3377 (1990); and Sato, F., et al., J. Org. Chem., 53, 5590 (1988)).
U.S. Pat. No. 4,873,360 to Johnson et al also describes another route to the cyclopentanoids, particularly the prostaglandins. This patent describes useful target PGs for the present invention.
The .alpha.-haloenones are disclosed for use in the synthesis of R.alpha.-cyclopentenone intermediates capable of transition-metal catalyzed cross-coupling with the .alpha.-sidechain using a process described by the inventor and co-workers in Johnson, C. R., et al., Tetrahedron Lett., 33, 917 (1992).